Why Vitamin B12 Deficiency Should be on your Radar Screen

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Why Vitamin B12 Deficiency Should Be
on Your Radar Screen
A Continuing Education Update
Course WB1349
Prepared for the
National Center on Birth Defects and Developmental Disabilities
Centers for Disease Control and Prevention
by
Marian L. Evatt, MD1
Patricia W. Mersereau, MN, CPNP2
Janet Kay Bobo, PhD3
Joel Kimmons, PhD4
Jennifer Williams, MSN, MPH, FNP-BC5
The findings and conclusions in this report are those of the authors
and do not necessarily represent the views of the
Centers for Disease Control and Prevention.
1
Department of Neurology, Emory University, Atlanta, Georgia.
SciMetrika, LLC, Atlanta, Georgia.
3
Battelle Centers for Public Health Research and Evaluation, Atlanta, GA and Seattle, Washington.
4
National Center for Chronic Disease Prevention and Health Promotion, CDC, Atlanta, Georgia.
5
National Center on Birth Defects and Developmental Disabilities, CDC, Atlanta, Georgia.
2
i
Vitamin B12 Deficiency
Contents
Goal and Objectives .................................................................................1
Accreditation ...........................................................................................2
Introduction ............................................................................................3
Case Studies ............................................................................................6
Natural History and Prevalence of Vitamin B12 Deficiency......................14
Risk Factors for Vitamin B12 Deficiency ..................................................20
Manifestations of Low Vitamin B12 Levels ..............................................23
Screening Patients .................................................................................27
Detection and Diagnosis ........................................................................28
Managing Patients With Evidence of a Vitamin B12 Deficiency................35
Prevention of Vitamin B12 Deficiencies...................................................40
Summary ...............................................................................................42
References .............................................................................................43
References for Text in Boxes .................................................................49
Appendix A: Answers to Case Study Questions ......................................51
Appendix B: Additional Articles on Vitamin B12 Deficiency .....................53
Appendix C: Evaluation Questionnaire, Pretest, and Posttest ................56
2/11/2010
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Vitamin B12 Deficiency
Figure and Tables
Figure 1. The Biochemical Role of Cobalamin........................................ 16
Table 1. Neurologic and Psychiatric Symptoms of Vitamin B12
Deficiency and Parkinson Disease (PD) ................................... 13
Table 2. Typical Stages in the Development of a
Vitamin B12 Deficiency .............................................................. 17
Table 3. Prevalence of Vitamin B12 Serum Levels for the U.S.
Population By Age, National Health and Nutrition Examination
Survey 2001вЂ“2004
вЂ¦вЂ¦вЂ¦вЂ¦вЂ¦вЂ¦вЂ¦вЂ¦вЂ¦вЂ¦вЂ¦ 19
Table 4. Prevalence of National Health and Nutrition Examination Survey
Participants With Biochemically Defined Vitamin B12 Deficiency*
By Age Group, United States, 2001вЂ“2004 вЂ¦вЂ¦вЂ¦вЂ¦вЂ¦вЂ¦вЂ¦вЂ¦вЂ¦вЂ¦вЂ¦ 31
Table 5. Tailored Diagnostic Approach for Vitamin B12 DeficiencyвЂ¦вЂ¦вЂ¦34
Table 6. Examples of Treatment Regimens for Vitamin B12 DeficiencyвЂ¦38
Disclosure
CDC, planners, and other content experts wish to disclose
they have no financial interests or other relationships with the
manufacturers of commercial products, suppliers of commercial
services, or commercial supporters.
This module will not include any discussions of the unlabeled use
of a product or a product under investigational use.
2/11/2010
iii
Why Vitamin B12 Deficiency
Should Be on Your Radar Screen:
A Continuing Education Update
Goal and Objectives
The goal of this continuing education activity is to
increase the number of primary care providers
(physicians and midlevel providers) who prevent, detect,
and treat vitamin B12 deficiencies among their high-risk
patients.
After completing this continuing education material, you
should be able to
вЂў
вЂў
вЂў
вЂў
вЂў
вЂў
Describe the prevalence in the United States of
vitamin B12 deficiency among adults 51 years of
age or older.
List three neurologic effects of a vitamin B12
deficiency.
List three hematologic effects of a vitamin B12
deficiency.
Identify the most common presentation of a
vitamin B12 deficiency.
Discuss the changes in absorption of vitamin B12
that occur with age.
List at least two pharmacologic options for
treatment of a vitamin B12 deficiency.
2/11/2010
1
Vitamin B12 Deficiency
Accreditation
Continuing Medical Education (CME): This
activity for 1.5 credits is provided by the Centers
for Disease Control and Prevention (CDC),
accredited by the Accreditation Council for
Continuing Medical Education to provide category 1
credits towards the American Medical Association
(AMA) PhysicianвЂ™s Recognition Award.
Continuing Nursing Education (CNE): This
activity for 1.5 contact hours is provided by CDC,
which is accredited as a provider of continuing
education in nursing by the American Nurses
Credentialing CenterвЂ™s Commission on
Accreditation (ANCC).
Registration
To register for the course and receive free continuing
education credit:
п‚·
п‚·
п‚·
п‚·
п‚·
п‚·
п‚·
Go to http://www.cdc.gov/tceonline..
Log in as a participant (note: the first time you use
the online system you will need to log in as a new
participant and create a participant profile).
Find the course by searching the catalog using the
following course number: WB1349.
You will need to enter the verification code (B12)
to complete the course.
Select the type of credit you wish to receive and
register for the course.
Take the examination and complete the course
evaluation.
Print your continuing education certificate.
To receive continuing education credit, you must
complete the entire course, take the post-test, and
complete the evaluation online.
During this lesson, you will find highlighted
terms. Roll your mouse over each term for
further information.
2
Vitamin B12 Deficiency
Introduction
Vitamin B12 (cobalamin) deficiency should be on your
radar screen for several reasons. Prevention, early
detection, and treatment of vitamin B deficiency are
important public health issues, because they are
essential to prevent development of irreversible
neurologic damage which can impact quality of life.
Although most health care providers already recognize
the occasional person who presents with obvious signs
and symptoms, they are far less likely to screen and
diagnose the majority of patients who have a subclinical
or mildly symptomatic vitamin B12 deficiency. Vitamin
B12 deficiency is more common among older adults than
many health care providers realize. Unpublished
analysis at the Centers for Disease Control and
Prevention (CDC) of laboratory data from communitybased samples of U.S. adults 51 years of age or older
suggest about 1 (3.2%) of every 31 persons have serum
vitamin B12 levels below 200 picograms per milliliter
(pg/mL).
Vitamin B12 has profound effects on human health.
Adequate body stores are essential for several crucial
neurologic and hematologic functions. Delays in the
diagnosis and treatment of vitamin B12 deficiencies can
lead to development of severe, irreversible neurologic
damage.
The clinical importance of vitamin B12 was established
over 50 years ago, when ingesting raw animal liver (the
primary storage organ for vitamin B12) was found to be
an effective treatment for pernicious anemia. Research
has shown that the water-soluble vitamin B12 is required
for the completion of several biochemical processes (see
Figure 1).
The following five top things to remember about vitamin
B12 in primary care practice summarize the implications
of these and other cobalamin-related findings.
3
Vitamin B12 Deficiency
The top five things to remember
about vitamin B12
1. Vitamin B12 deficiencies occur in adults 51 years of
age or older at a frequency of 1 (3.2%) in every 31
persons, and manifest as serum vitamin B12 levels
below the cutpoint of 200 picograms per milliliter.
2. All patients with unexplained hematologic or
neurologic signs or symptoms should be evaluated for
a vitamin B12 deficiency. If found, the cause should
should be determined.
3. Today, megaloblastic anemia is most likely due to
vitamin B12 deficiency and needs prompt evaluation.
In the United States, folic acid fortification has made
folate deficient megaloblastic anemia a very rare
condition.
4. Although the bodyвЂ™s ability to absorb naturally
occurring vitamin B12 decreases with age, most people
can readily use the synthetic form of cobalamin.
5. All people 51 years of age or older should get most of
their daily vitamin B12 through supplements
containing vitamin B12 or foods fortified with
vitamin B12.
4
Vitamin B12 Deficiency
This update has been prepared and organized to address
four questions pertinent to primary health care
providers:
п‚·
Why should I be concerned about my patientвЂ™s
vitamin B12 status?
o Introduction
o Case studies
o Natural history and prevalence of vitamin B12
deficiencies
o Manifestations of low vitamin B12 levels
п‚·
Which of my patients are at high risk for vitamin B12
deficiency?
o Risk factors for a vitamin B12 deficiency
п‚·
How do I detect and diagnose a vitamin B12
deficiency?
o Screening patients
o Detection and diagnosis
п‚·
How should I manage a patient with evidence of
vitamin B12 deficiency?
o Managing patients with evidence of a vitamin
B12 deficiency
o Preventing vitamin B12 deficiencies
5
Vitamin B12 Deficiency
Case Studies
The following case studies are not actual patients. They
combine elements from different cases to emphasize
important aspects of vitamin B12 deficiency.
Case Study 1
Presentation
During a checkup for hypertension, a 65-year-old female
reports a 2-month history of tiredness, feeling faint from
вЂњgetting up too fastвЂќ, and вЂњmemory problemsвЂќ.
Case Study Question 1
Do any of the presenting complaints raise your index of
suspicion about a possible vitamin B12 deficiency? If so,
why?
History
On review of systems, she reports difficulty
concentrating, fatigue, feeling faint when she stands
quickly, and vague gastrointestinal discomfort with some
decrease in appetite.
She denies any history of previous trauma, diplopia,
dysphagia, vertigo, vision loss, loss of consciousness,
back pain, or symptoms of bowel or bladder dysfunction.
Her family history is negative for neurologic, psychiatric,
and autoimmune diseases. Her medications include an
antihypertensive, as well as an occasional antiinflammatory drug for episodic headaches. Her social
history reveals a single woman who smokes about onehalf pack of cigarettes per day, drinks alcohol only
socially, and denies illicit drug use. She has a high
school education and, until recently, had worked in the
office of a trucking company.
6
Vitamin B12 Deficiency
Case Study Question 2
What risk factors does this woman appear to have for a
vitamin B12 deficiency?
Physical Examination
Pale 65 y.o. WF who appears well-nourished, alert, and
oriented.
Vital Signs
T-98.6, HR-76, R-18, B/P-130/80 supine
and 95/52 upon standing,
Height/Weight 5вЂ™4вЂќ/120 lbs.
Head
Normocephalic; oropharynx clear but
pale; palpebral conjunctivae pale.
Neck
Supple, full active and passive ROM
without pain, without audible bruits; no
lymphadenopathy; no thyromegaly
Back
No spine tenderness
Lungs
Clear to auscultation
Heart
Regular rate and rhythm; no murmurs
Abdomen
Soft, nontender; no organomegaly
Rectal
Normal rectal tone; no fissures
Extremities
No clubbing, cyanosis, or edema; FROM
Skin
Pale; no rash
The general physical examination is unremarkable
except for orthostatic hypotension and a weight loss of 3
pounds since her last visit 6 months ago. She is alert
and oriented times three. Her Mini-Mental Status Exam
score is 26 out of 30. She misses one point on serial 7s
and is able to recall three of three items. There is
evidence of bilateral mildly diminished vibration and
proprioception. Her reflexes are 3+/4+ throughout, with
negative Babinski reflex.
Cranial
Nerves
IIвЂ”Visual acuity 20/25 in both eyes
(corrected); normal fundoscopic
examination; visual fields intact with no
central scotoma
III, IV, VIвЂ”Extraocular movements
intact; pupils equal, round, and reactive
to light with no afferent pupillary defect
V, VII, XIIвЂ”Intact facial sensation; intact
7
Vitamin B12 Deficiency
masseter motor strength, without
dysarthria; tongue protruded in midline
VIIIвЂ”Hearing grossly normal
XI, XвЂ”Swallowing intact
XIвЂ”Muscle strength equal bilaterally
Motor
Normal muscle bulk; muscle strength 5/5
in all muscle groups
Cerebellar
Normal finger-to-nose, heel-to-shin, and
rapid alternating movements
Case Study Questions
3. Does the fact that she appears to be вЂњwell-nourishedвЂќ
indicate she is unlikely to have a vitamin deficiency? Why
or why not?
4. Are there any aspects of her physical examination that
suggest a vitamin B12 deficiency?
5. Given her history and physical examination findings,
what laboratory test(s) would you order?
Laboratory Studies
You order routine laboratory studies, which include
complete blood count (CBC) with smear and chemistry
screen. In addition, you order a serum vitamin B12 level
to investigate further the etiology of her fatigue and pale
mucosa. Results from the CBC and smear reveal a
borderline macrocytic anemia. The chemistry panel is
within normal limits. The serum vitamin B12 level you
requested is 215 picograms per milliliter (pg/mL). This
level is considered within a вЂњnormal rangeвЂќ by some
laboratories, but you take into account her other signs
and symptoms and request confirmatory testing with
8
Vitamin B12 Deficiency
methylmalonic acid (MMA) and homocysteine (Hcy)
levels.
Results of Confirmatory Testing
Both her MMA and Hcy levels are elevated. Her MMA is
greater than 0.5 micromoles per liter (Ојmol/L), and her
Hcy is greater than 17 Ојmol/L, confirming your suspicion
that this patient has a vitamin B12 deficiency.
You decide to investigate the cause of her vitamin B12
deficiency. Although she denies a history of pernicious
anemia in her family and she has had no previous
indication of autoimmune diseases, you order an antiintrinsic factor (IF) antibody test that confirms the
presence of pernicious anemia.
Management
You explain that with the diagnosis of pernicious anemia
she will have to continue vitamin B12 therapy for the
remainder of her life, and you make a note on her chart
to assess her compliance at each visit. You also advise
her to inform her family of the diagnosis because there
is possibly a genetic component.
You start her on vitamin B12 intramuscular (IM)
injections. She gets IM cyanocobalamin 1,000
micrograms (Вµg) two times per week for 2 weeks and
then switches to oral vitamin B12 1,000 Вµg daily
thereafter. Almost immediately after the initiation of
injections, she reports improved concentration. Within 2
weeks, she notes less fatigue and normal appetite.
Case Study 2
Presentation
An 85-year-old female with a 15-year history of
Parkinson disease (PD) is seen for her regularly
scheduled follow-up with her neurologist.
History
On review of systems, family members report that she
has become more withdrawn and irritable during the last
9
Vitamin B12 Deficiency
6 months. They also report that activities she previously
accomplished without difficulty, such as going to church,
seem to exhaust her. She acknowledges this symptom,
stating that she feels her stamina is much lower than at
the time of the last visit.
She and her family do not report an appreciable
difference in or worsening of her motor symptoms, but
they do report that she has had some hallucinations in
the form of seeing farm animals periodically in her room.
Her current medications include Stalevoв„ў(carbidopa,
levodopa, and entacapone), amantadine, EvistaВ®
(raloxifene hydrochloride), EffexorВ® XL (venlafaxine
hydrochloride), DetrolВ® LA (tolterodine tartrate),
MirapexВ® (pramipexole dihydrochloride), and AmbienВ®
(zolpidem tartrate). She denies any obsessive or
compulsive behaviors or any recent trauma, but she
does admit having a decreased appetite and eating little
or no meat. Her family describes her nutritional intake
as poor, stating that she is just getting by on вЂњtea and
toastвЂќ.
Her social history reveals a widowed elderly woman who
lives with her son and daughter-in-law. She had lived
independently until 5 years ago, when completing her
activities of daily living (ADLs) became too difficult. She
currently has a home health nurse visit once a day to
assist with ADLs and noontime medications while her
family is at work.
Physical Examination
A general examination reveals a frail, thin female with
skin irritation and slight amount of saliva evident at the
right corner of her mouth (the side where her PD
symptoms are more pronounced). She has slight
puffiness but no pitting of her ankles bilaterally.
A neurological examination reveals that she is alert and
oriented to person, place, and year. She remembers 3
out of 3 items, but can recall only one of three items 3
minutes later. She has definite facial masking and a
decreased blink rate. Cranial nerve examination reveals
moderate hypophonia (low voice volume) and an
intermittent tremor. She is moderately stooped with a
slight tilt to the right, and she has difficulty rising from a
10
Protein intake among patients
with Parkinson disease (PD)
might interfere with levodopaвЂ™s
clinical benefit. Thus, PD patients
might inadvertently increase their
risk of vitamin B12 deficiency by
avoiding meat, the dietary source
of vitamin B12.
Vitamin B12 Deficiency
chair without assistance, even though her strength is
normal. She has a mild-to-moderate intermittent resting
tremor, worse on her right side. Sensory examination
reveals decreased vibratory thresholds in both legs up to
her ankles. Reflexes are 3+ out of 4 with crossed
adductor spread in her legs, and her plantar reflex
shows positive Babinski bilaterally.
Laboratory Studies
Her neurologist orders some routine laboratory studies,
including a CBC with smear and chemistry panel. In
addition, the neurologist decides to get a serum B12 level
because she is considered at high risk for a vitamin B12
deficiency, and many of the symptoms of PD also can be
attributed to vitamin B12 deficiency.
Results from the CBC with smear demonstrate no
evidence of anemia. The chemistry panel is within
normal limits, with the exception of a slightly elevated
serum creatinine (1.5 milligrams per deciliter). Her
serum B12 level is 225 pg/mL, within the laboratoryвЂ™s
normal range of 180вЂ“900 pg/mL. The neurologist
considers this value as вЂњlow-normalвЂќ and requests
confirmatory testing with MMA and HCY levels.
Slightly elevated creatinine
could indicate age-related
changes in renal function,
dehydration, or mild renal
insufficiency from other
causes.
Results of Confirmatory Testing
Her HCY is elevated at 18 Вµmols/L; however, her
neurologist recognizes that this finding alone is not
considered diagnostic, given that levodopa has been
known to alter HCY levels.
Conversions
1,000 nmol/L* = 1 Вµmol/L
Her MMA is borderline at 0.38 Вµmol/L but, again, this
finding is not diagnostic.
376 nmol/L = 0.376 Вµmol/L
Although PD can explain most of her symptoms, vitamin
B12 deficiency can also account for some of them. Her
age is a risk factor for atrophic gastritis, and her diet
seems to be deficient in protein so both malabsorption
and malnutrition could contribute to borderline vitamin
B12 deficiency.
11
*nanomols per liter
Vitamin B12 Deficiency
Management
Given the uncertain nature of the test results, her
neurologist discusses vitamin B12 supplementation with
her. She expresses disinterest in oral supplementation,
stating вЂњIf I have to take one more pill, I will scream.вЂќ
Because the laboratory findings are ambiguous, the
neurologist and she agree to monitor her status rather
than start injection therapy immediately.
On her return visit 6 months later, her serum vitamin B12
is 189 pg/mL, and both her Hcy and MMA levels have
increased. Her neurologist orders antiparietal cell
antibody and anti-intrinsic factor antibody tests to rule
out pernicious anemia. Both tests are negative. She is
started on 1,000 Вµg of IM cyanocobalamin for 5 days,
followed by monthly injections of 1,000 Вµg of IM
cyanocobalamin. Her neurologist makes arrangements
for the home health nurse to administer the injections.
At the next visit, the patient and her family report that
she is less fatigued, less irritable, and less withdrawn.
There is no worsening of motor symptoms; however, she
still experiences occasional hallucinations.
12
Vitamin B12 Deficiency
Table 1. Neurologic and Psychiatric Symptoms of Vitamin B12
Deficiency and Parkinson Disease (PD)
Vitamin
PD
B12
Deficiency
Autonomic
Impotence, urinary or fecal incontinence
Orthostatic hypotension
+
+
+
+
+
+
+
+*
+
+*
+
+
+
+
+
+
-
+
+
+
Cerebral
Dementia, memory loss, cognitive impairment
Depression
Psychosis
Myelopathic
Subacute combined degeneration
Ataxia
Spasticity
Lehrmitte sign (electric-shockвЂ“like sensations in the
spine)
Abnormal GaitвЂ Spastic
Shuffling
Constitutional
Fatigue
*Seen in PD or resulting from dopaminergic PD treatment), or
both
вЂ Note gait abnormalities do not always appear вЂњtypicalвЂќ of
textbook descriptions
13
Vitamin B12 Deficiency
Natural History and Prevalence of
Vitamin B12 Deficiency
вЂњAlthough elderly people with low vitamin B12 status frequently
lack the classical signs and symptoms of vitamin B12 deficiency,
e.g. megaloblastic anemia, precise evaluation and treatment in
this population is important.вЂќ Baik and Russell, 1999
The case studies illustrate two important facts about
vitamin B12 (cobalamin). First, low vitamin B12 levels can
have profound effects on patient well-being. Although
most patients with a vitamin B12 deficiency are in a
subclinical stage(1-7) and do not present with symptoms
or complaints such as those of the case study patients,
some patients might be at risk for developing serious
sequelae if the deficiency is not detected and the
patients followed with reassessment, prophylaxis, or
treatment, as needed. Second, treatment is safe and
remarkably effective if provided before permanent
damage occurs. Understanding the biochemistry of
vitamin B12, the problems that might develop when
cobalamin body stores are depleted, and current
treatment strategies can help clinicians prevent
significant morbidity among their patients.
The nutritional value of vitamin B12 was initially
established in the first half of the 20th century, when
ingesting raw animal liver (the primary storage organ for
this nutrient) was found to be an effective treatment for
pernicious anemia.(8) Humans cannot manufacture
cobalamin and must consume it on a regular basis.
Vitamin B12 is a water-soluble compound that is naturally
available for human use only through ingestion of animal
proteins, such as beef, poultry, fish, eggs, and dairy
products. Unfortified, plant-based foods do not contain
vitamin B12.(2, 9, 10)
14
Vitamin B12 is naturally
available for human use only
through ingestion of animal
proteins. Unfortified plantbased foods do not contain
vitamin B12.
Vitamin B12 Deficiency
There are several important points about cobalamin
absorption:
п‚·
п‚·
п‚·
п‚·
п‚·
It occurs primarily during the active digestion of
animal proteins in the stomach and terminal ileum,
and it depends on the availability of adequate
amounts of a number of compounds, including the R
protein (haptocorrin from saliva), gastric acid, pepsin,
and intrinsic factor (IF).(2, 3)
Gastric acid is needed to digest animal protein. When
the ability to secrete that acid is lost, a person cannot
break down the protein to release vitamin B12 from
food and can absorb only crystalline (synthetic)
vitamin B12.(2)
Loss of IF in pernicious anemia results in an inability
to absorb vitamin B12. People with pernicious anemia
must be treated with parenteral cyanocobalamin or
high doses of oral cobalamin
(1,000 micrograms [Вµg] daily).(2, 11)
About 1% of large oral doses of vitamin B12 passively
diffuses into the bloodstream from the small
intestine.(2, 10)
If any aspect of the digestion sequence begins to fail
and malabsorption develops, the body can draw on
the large amounts of vitamin B12 stored in the liver,
so overt symptoms might not develop for several
years.(2, 10, 12) However, with certain conditions,
vitamin B12 deficiency might develop over a shorter
period of time (months).
Adequate serum levels of cobalamin are crucial to
complete three enzymatic processes (Figure 1).
п‚· Methylcobalamin is a cofactor necessary to convert
homocysteine (Hcy) to methionine. Thus, vitamin
B12 deficiency increases Hcy.(1, 12, 13)
п‚· The cofactor adenosylcobalamin is required for the
conversion of methylmalonyl coenzyme A to
succinyl coenzyme A.(2, 10)
п‚· Methylcobalamin is needed to convert 5methyltetrahydrofolate to tetrahydrofolate and is
necessary for DNA and red blood cell production.
15
Pernicious anemia is an
autoimmune disease in
which antibodies attack
gastric cells, resulting in
impaired production of
intrinsic factor that is
critical for absorption of
vitamin B12.
Vitamin B12 Deficiency
Figure 1. The Biochemical Role of Cobalamin
Vitamin B12 deficiencies often, but not always, develop
gradually over many years and are accompanied by a
slow and varied onset of nonspecific symptoms. Carmel
describes vitamin B12 deficiency in two states: clinical
and subclinical.(1) Clinical deficiency manifests with
hematologic or neurologic signs and symptoms,
cobalamin levels <200 picograms per milliliter (pg/mL),
and levels for Hcy and methylmalonic acid (MMA) that
are usually elevated. Subclinical deficiency includes
absent signs and symptoms, although some patients
might have subtle changes on neurologic examination;
low to low-normal cobalamin levels (200вЂ“350 pg/mL);
and at least one metabolic abnormality (elevated Hcy or
elevated MMA), usually mild. You are likely to encounter
more of your patients in the asymptomatic subclinical
stage of vitamin B12 deficiency rather than in the classic,
overtly apparent clinical vitamin B12 deficiency.(1, 12,
14) The challenge for you is how and when to respond to
a patient without the typical signs and symptoms of
clinical vitamin B12 deficiency.
16
Vitamin B12 Deficiency
The first to conceptualize the natural history of a vitamin
B12 deficiency, Herbert noted that vegetarians with
dietary vitamin B12 insufficiency progressed through four
stages: serum depletion; cell depletion; biochemical
deficiency (defined as elevated levels of Hcy and MMA);
and, finally, the classic signs and symptoms of clinical
deficiency, such as anemia (Table 2).(9, 15)
Table 2. Typical Stages in the Development of a Vitamin
B12 Deficiency. Herbert, 1994
Stage
Manifestation
Comment
I
Circulating serum B12
levels depleted
Patients are typically
asymptomatic and can
remain in this stage for
several years.
II
Cellular stores of B12
are depleted
Patients can remain
asymptomatic. This stage
can also continue for several
years.
III
Evidence of biochemical deficiency via
increases in serum
homocysteine and
methylmalonic acid
Vitamin B12 is required for
the conversion of these
compounds.
IV
Clinical signs and
symptoms apparent
The spectrum of clinical
manifestations is broad and
the sequence of symptom
development varies
markedly.
Although this model provides a useful perspective,
untreated patients will not necessarily advance through
the stages chronologically or linearly. Progression to a
later stage is not inevitable, and some patients with
evidence of an early stage deficiency might have normal
laboratory values when retested.(11) Malabsorption of
food-derived cobalamin because of decreased gastric
acid production is a more likely reason for vitamin B12
deficiency, while malabsorption of cobalamin because of
lack of IF in pernicious anemia is a less prevalent
cause.(3)
17
Vitamin B12 Deficiency
Prevalence of Vitamin B12 Deficiency
The true prevalence of vitamin B12 deficiency tends to be
underestimated for several reasons. The common
misconception that most vitamin B12 deficiencies are due
to inadequate dietary intake might lead to overlooking
important high-risk groups. Older adults who routinely
consume meat and other animal proteins can still be
vitamin B12 deficient due to malabsorption. Clinical
vitamin B12 deficiencies are relatively rare. Most
patients are far more likely to have mild, subclinical
vitamin B12 deficiency.(1)
Most prevalence estimates are based solely on serum
vitamin B12 results. Confusion can arise because
cobalamin values are measured in picomoles per liter
(pmol/L) in some research studies, while clinical
laboratories express values in picograms per milliliter
(pg/mL) or nanograms per liter (ng/L). The most
frequently reported threshold value is 200 pg/mL (148
pmol/L).(1, 16) Studies that have established higher
cutpoints invariably have reported higher prevalence
estimates. In the research literature, some investigators
have used diagnostic algorithms that combine serum B12
results with one or more additional laboratory findings,
typically either serum Hcy or MMA.(1, 4, 17, 18)
Depending on the approach used, the additional test
findings have raised(4, 18, 19) or lowered(6, 19, 20) the
observed prevalence of vitamin B12 deficiency compared
with findings based solely on serum vitamin B12 levels.
Unpublished data from the National Health and Nutrition
Examination Survey (NHANES) 2001вЂ“2004 in Table 3
stratified by age have estimated that 1 (3.2%) of every
31 adults 51 years of age or older in the United States
has a low vitamin B12 serum level. Most of these people
are ambulatory and do not have overt symptoms of
vitamin B12 deficiency.
18
Conversions
ng/L = pg/mL
pmol/L = pg/mL x 0.738
pg/mL = pmol/L Г· 0.738
Keep in mind that ng/L has
the same value as pg/mL but
conversion to pmol/L requires
multiplication of pg/mL by
0.738 (200 pg/mL x 0.738 =
148 pmol/L).
Vitamin B12 Deficiency
Table 3. Prevalence of Vitamin B12 Serum Levels for
the U.S. Population by Age, National Health and
Nutrition Examination Survey 2001вЂ“2004
Vitamin B12
Serum Level
9вЂ“13
years
of age
14вЂ“18
years
of age
19вЂ“30
years
of age
31вЂ“50
years
of age
в‰Ґ 51
years
of age
0
0.2%
0.2%
0.5%
1.2%
151вЂ“200
pg/mL
0.1%
0.6%
1.5%
1.0%
2.0%
201вЂ“250
pg/mL
0.6%
2.5%
5.2%
6.1%
5.1%
251вЂ“300
pg/mL
1.6%
5.4%
7.9%
6.9%
6.2%
301вЂ“350
pg/mL
4.2%
9.4%
11.3%
10.7%
8.9%
351вЂ“400
pg/mL
5.4%
9.2%
13.1%
13.5%
10.7%
> 400 pg/mL
88.0%
72.7%
60.8%
61.2%
65.8%
в‰¤ 150 pg/mL
Those prevalence figures are supported by other
population-based studies. The Framingham study with a
cohort of noninstitutionalized adults 67 through 96 years
of age found that 5.3% of the participants had serum
vitamin B12 levels <200 pg/mL.(4)
As summarized in the pop-up box, inclusion criteria and
differences in laboratory testing make prevalence
estimates from clinic-based studies difficult to compare
with population-based estimates.
19
One study of outpatients in
Oklahoma using a serum B12
threshold value of <200 pg/mL
found that 6% were deficient.
(Barnard, 1998) In Seattle,
Washington, researchers
determined that 13% of the
outpatient study participants
were deficient, using values of
B12 в‰¤300 pg/mL and MMA >271
nanomoles per liter
(nmol/L).(Rajan, 2002) When
the threshold for B12 was set at
300 pg/mL and two metabolic
tests were included, 14.5% of
participants were considered
deficient in a sample of older
outpatients in Denver,
Colorado. (Pennypacker, 1992)
One conservative study used a
threshold value of 180 pg/mL
and found that 5.2% of elderly
inpatients and outpatients were
diagnosed as vitamin B12
deficient. (Matchar, 1994)
Vitamin B12 Deficiency
Risk Factors for
Vitamin B12 Deficiency
вЂњThe clinical indications (for cobalamin deficiency) are of
prime importance since routine screening tests, such as
the blood count, are not always abnormal. The same
criteria apply to both sexes and to all age groups,
including preterm infants and children.вЂќ Amos, 1994
Patient characteristics that increase the likelihood of a
vitamin B12 deficiency can be divided broadly into
demographic and behavioral characteristics that increase
the risk of inadequate dietary intake (malnutrition) and
physiologic factors that increase the risk of
malabsorption. Some factors, such as advanced age,
might increase the risk of both malnutrition and
malabsorption. In the United States, most cases of
vitamin B12 deficiency are due to malabsorption rather
than inadequate intake. We will review the more obvious
demographic and behavioral вЂњred flagsвЂќ of aging and
strict vegetarianism and vegan diets and then
summarize the less readily apparent but more common
physiologic factors that can affect absorption.
Demographic and Behavioral Risk Factors
The risk of developing a vitamin B12 deficiency increases
with age.(1, 6, 16, 21-23) The elderly, defined as
individuals 65 years of age or older, are more likely to
develop a vitamin B12 deficiency because they are at risk
for both malabsorption and malnutrition. The frail
elderly, especially, might have dietary insufficiency for a
number of reasons, including cognitive dysfunction,
social isolation, mobility limitations, and poverty.
In contrast to the importance of age, other demographic
characteristics, including sex, race, and ethnicity, are not
as important in predicting vitamin B12 deficiency. While
several studies have found that mild cobalamin
deficiency is most common among elderly White men
and least common among Black or African-American and
Asian-American women, (2, 3, 16, 24) the differences
20
In the United
States, most cases
of vitamin B12
deficiency are due
to malabsorption.
Vitamin B12 Deficiency
are not sufficient to support sex- or race-specific nutrient
recommendations.(10)
A patient characteristic that should always raise the
index of suspicion is long-term adherence to a strict
vegetarian or vegan diet,(10, 16, 25, 26) because vegan
diets exclude all forms of animal protein, including eggs
and dairy products. Thoughtfully planned vegetarian
diets that include eggs, milk, and yogurt can provide
adequate amounts of vitamin B12. Short-term adherence
to strict vegetarian and vegan diets might not cause a
problem because of the large amount of vitamin B12
typically stored in the liver. However, it is prudent to
advise all vegetarian and vegan patients, particularly if
they are elderly or anticipating a pregnancy, to consume
synthetic cobalamin daily, either by taking a supplement
containing vitamin B12 or eating a serving of vitamin B12вЂ“
fortified grain products.(10) The requirement for vitamin
B12 increases for pregnant and lactating women.(10) To
review the vitamin B12 content of a variety of vegetarian
and vegan foods, see
http://www.nal.usda.gov/fnic/foodcomp/search/.
Physiologic Factors
Malabsorption is the physiologic cause of vitamin B12
deficiency and can result from a number of conditions.
Frequently mentioned are pernicious anemia; (7, 24)
atrophic gastritis;(3, 10, 27) gastric surgery (e.g., ileal
resection and gastrectomy);(11, 16, 28) presence of a
cobalamin-utilizing fish tapeworm such as the
Diphyllobothrium latum;(2, 29) and other concurrent
diseases such as Crohn disease, HIV infection,(30-32)
celiac sprue,(33, 34) and bacterial overgrowth in the
small intestine.(35) Rare cases have been attributed to
anesthetic nitrous oxide exposure.(2, 36)
Among the elderly, atrophic gastritis and pernicious
anemia are the main causes of malabsorption. Atrophic
gastritis often develops as people age. With resulting
hypochlorhydria and achlorhydria, the body does not
produce enough pepsin and hydrochloric acid to release
from protein the food-bound vitamin B12. In pernicious
anemia, missing IF needed to attach B12 in the small
intestine impairs the uptake of vitamin B12.
21
Inadequate absorption
п‚·
Pernicious anemia
п‚·
Atrophic gastritis
п‚·
Small intestinal bacterial
overgrowth
п‚·
Gastrointestinal surgery
(e.g., ileal resection or
gastrectomy)
Presence of a cobalaminп‚·
utilizing fish tapeworm,
such as Diphyllobothrium
latum
п‚·
Crohn disease
п‚·
HIV infection
п‚·
Celiac sprue
Nitrous oxide causes the
inactivation of vitamin B12,
which might result in acute
hematologic or neurologic
complications of vitamin B12
deficiency. Because nitrous
oxide is a commonly used
anesthetic in surgery, people
at risk (e.g., the elderly)
should be monitored for a
developing symptomatic
vitamin B12 deficiency.
Vitamin B12 Deficiency
Undiagnosed and untreated pernicious anemia affects
1%вЂ“2% of the elderly population.(24)
22
Vitamin B12 Deficiency
Manifestations of
Low Vitamin B12 Levels
вЂњAlthough some clinical expressions remain mysterious,
especially the neurological dysfunction, our view of
cobalamin deficiency has expanded beyond the question
of megaloblastic anemia.вЂќ
Carmel, 2000
No single symptom, or cluster of symptoms, has been
uniquely associated with inadequate levels of vitamin
B12. Among older adults, the most frequently reported
symptoms of vitamin B12 deficiency are hematologic or
neurologic in nature, but gastrointestinal and
possibly vascular symptoms are also common. The
typically nonspecific manifestations of a vitamin B12
deficiency underscore the importance of encouraging all
older adults to consume the synthetic form of the
vitamin each day. Recent concerns have also been raised
about potential adverse effects on infant growth and
development in exclusively breastfed babies of
mothers who adhere to a strict vegan diet.(11, 16)
While this situation is rare in the United States, sequelae
are often severe and irreversible in these children.
Hematologic Manifestations
Common symptoms associated with hematologic
pathology include skin pallor, weakness, fatigue,
syncope, shortness of breath, and palpitations.(2, 10) A
classic hematologic sign of severe vitamin B12 deficiency
is megaloblastic anemia.(2) Hematologic manifestations
might also be due to folate deficiency. However, since
1998, the U.S. Food and Drug Administration has
required fortification of all enriched grain and cereal
products with 140 micrograms (Вµg) of folic acid per 100
grams of cereal grain product,(37) and that fortification
of the U.S. food supply essentially has eliminated the
prevalence of folate deficiency.(21) Today, in the United
States, a case of megaloblastic anemia most likely is due
to vitamin B12 deficiency until proven otherwise.
Although vitamin B12 deficiency is not always
accompanied by hematologic changes, the majority of
23
Today, in the United
States, megaloblastic
anemia is most likely
due to a vitamin B12
deficiency until proven
otherwise.
Folic acid fortification does not
have an effect on the
prevalence of megaloblastic
anemia attributable to vitamin
B12 deficiency. Very high doses
of folic acid (>5,000 Вµg each
day) can correct the
hematologic manifestations of
vitamin B12 deficiency; however,
the amount of folic acid
available through fortification as
specified by the U.S. Food and
Drug Administration (FDA) is
not likely to affect a vitamin B12
deficiency-induced anemia
(FDA, 1996).
Vitamin B12 Deficiency
patients with clinical deficiency will have signs of
megaloblastic anemia. In various studies conducted
among patients with overt vitamin B12 deficiency, 56%вЂ“
77% of people had signs of macrocytosis or
anemia.(5, 38-41) Furthermore, some researchers
have found that the presence of neurologic
manifestations of a vitamin B12 deficiency might even be
correlated inversely with evidence of hematologic
effects.(10, 39, 42)
Many B12вЂ“deficient
patients do have
anemia or
macrocytosis.
Neurologic Manifestations
Common neurologic complaints include paresthesias
(with or without objective signs of neuropathy),
weakness, motor disturbances (including gait
abnormalities), vision loss, and a wide range of cognitive
and behavioral changes (e.g., dementia, hallucinations,
psychosis, paranoia, depression, violent behavior, and
personality changes). Tingling of the hands and feet is
perhaps the most common neurologic complaint.(2, 41,
42)
The pathology of vitamin B12 deficiency on the nervous
system is unknown.(7)
All patients with unexplained cognitive decline or
dementia should be assessed for a possible vitamin B12
deficiency.(41, 43-45) Several current case reports and
studies support the common practice of assessing
vitamin B12 levels during dementia workups.(41, 46-48)
Although only a minority (1.5%) of all dementia cases
are fully reversible following treatment,(49) many
dementias from other etiologies (e.g., Parkinson or
Alzheimer disease) are exacerbated when patients have
a concomitant low vitamin B12 level. The American
Academy of Neurology (AAN) has concluded that
because vitamin B12 deficiency is a likely comorbidity
among the elderly, and among patients with suspected
dementia in particular, it should be recognized and
treated. The AAN practice guideline states that B12 levels
should be included in routine assessments of dementia
among the elderly.(44)
24
All patients newly
diagnosed with
unexplained cognitive
decline or dementia
should be assessed for a
possible vitamin B12
deficiency.
Vitamin B12 Deficiency
Gastrointestinal Manifestations
Vitamin B12 deficiency might also manifest with
gastrointestinal complaints. Some frequently mentioned
symptoms include anorexia, flatulence, diarrhea, and
constipation.(7, 10, 36, 50) These symptoms can
develop among patients with a vitamin B12 deficiency
without accompanying anemia, macrocytosis, or overt
neurologic deficits. Glossitis, which is commonly thought
to be a cardinal sign of some anemias, is actually a
relatively rare manifestation of clinical vitamin B12
deficiency and is completely absent in subclinical vitamin
B12 deficiency according to Carmel (Carmel RA. New York
Methodist Hospital [personal communication] 20062007).
Vascular Manifestations
Both low vitamin B12 levels and low folate levels are
associated with elevated levels of homocysteine (Hcy).
Hyperhomocysteinemia increases the chance of
developing a vascular occlusion,(51) thus potentially
increasing the risk of coronary heart disease and
ischemic stroke. Although the association of coronary
heart disease or ischemic stroke with vitamin B12 or
folate deficiency has not been proven, the SEARCH
(Study of the Effectiveness of Additional Reductions in
Cholesterol and Homocysteine) study in the United
Kingdom is seeking to obtain evidence about the effect
of reducing Hcy on cardiovascular risk while treating
patients with 2 milligrams (mg) of folic acid plus 1 mg of
vitamin B12 daily. In addition, the SEARCH study is
looking at the efficacy and safety of two different
dosages of simvastatin in regard to risk reduction for
major cardiovascular events.(52) This randomized study
is scheduled to end in 2008 and should provide evidence
about the causal relationship of Hcy to cardiovascular
disease and about the value of folic acid and vitamin B12
supplementation, in addition to answering questions
about simvastatin therapy.
Effects on Infant Growth and Development
Although the previously cited hematologic, neurologic,
gastrointestinal, and cardiovascular consequences are
25
Nursing infants of
mothers who adhere to a
strict vegetarian or vegan
diet throughout their
pregnancy and while
breastfeeding might also
experience serious B12related deficiency effects.
Vitamin B12 Deficiency
typically observed among older patients, several cases of
significant vitamin B12 deficiencies among infants and
young children have been reported.(53-56) Low or
marginal vitamin B12 status among pregnant women
increases the risk for neural tube birth defects.(57)
Exclusively breastfed infants of mothers who adhere to
a strict vegetarian or vegan diet that excludes all animal
proteins might also experience serious effects related to
vitamin B12 deficiency.(50, 53, 54, 56) Clinical
manifestations among infants and young children are
widely varied, encompassing hematologic, neurologic,
and gastrointestinal symptoms. Some potential effects
include the following:
п‚· Failure to thrive
п‚· Hypotonia
п‚· Ataxia
п‚· Developmental delays
п‚· Macrocytosis or anemia
п‚· General weakness
Many of these effects will improve with prompt vitamin
B12 administration but, sometimes, irreversible
neurologic damage occurs before the diagnosis is made
and treatment is begun.(50, 53-56) Nursing infants of
vegan mothers can develop significant problems even
when the mother is not anemic or symptomatic in any
way.(50, 53, 55) It is important for you to ask pregnant
women and new mothers who breastfeed about their
diets.
26
Vitamin B12 Deficiency
Screening Patients
вЂњ. . . It is daunting and probably unnecessary to actively
seek out new asymptomatic cases [of vitamin B12
deficiency] by screening . . .вЂќ
Carmel, 2003
Most experts do not recommend community-based mass
screening programs for vitamin B12 deficiency, even
among highвЂ“risk groups, such as the frail elderly. For
example:
п‚· The U.S. Preventive Services Task Force has not
published formal recommendations on screening
asymptomatic older adults.
п‚· The major medical societies have no
recommendations on routine cobalamin screening.
п‚· The National Guideline Clearinghouse website has
no guidelines calling for periodic assessment in
asymptomatic patients. (However, if you provide
primary care to patients with dementia or altered
mental status and celiac sprue or other
gastrointestinal conditions, you might wish to
consult the website (http://www.guideline.gov) for
recommendations related to vitamin B12
monitoring among these highвЂ“risk groups.)
27
Vitamin B12 Deficiency
Detection and Diagnosis
вЂњIt is particularly important that the diagnosis of
cobalamin deficiency be established with a high degree
of certainty because cobalamin therapy almost always
must be given for the life-time of the patient.вЂќ
Stabler and Allen, 2004
Keeping vitamin B12 deficiency on your radar screen
means staying vigilant during your review of your
patientвЂ™s history and during the physical examination.
Watch for even subtle signs of neurologic or cognitive
impairment. Also, note any elements of the patientвЂ™s
history that might suggest potential malabsorption or
malnutrition, such as previously diagnosed pernicious
anemia, previous gastrointestinal surgery, vegan diet,
and advanced age. Maintain an especially high index of
suspicion of vitamin B12 deficiency in new patients who
report they were treated with vitamin B12 injections or
high doses of oral vitamin B12 supplements by a former
provider, but have since discontinued their use. Elderly
patients often fail to understand that a true
vitamin B12 deficiency due to malabsorption
requires lifelong treatment.
Early detection and prompt treatment of a vitamin B12
deficiency are essential to prevent development of
irreversible neurologic damage, but making an accurate
and timely diagnosis can be challenging. The list of
related signs and symptoms is long, varied, and nonspecific. Many risk factors have been identified, but
there are no known necessary or sufficient causes.
Complicating things further is the fact that because the
liver is a very efficient storage organ for vitamin B12,
even completely deficient diets in healthy adults might
not result in low serum vitamin B12 levels for several
years. Conversely, apparently healthy adults, especially
the elderly, consuming diets rich in naturally occurring
vitamin B12 can still develop a significant deficiency
because of undetected malabsorption. It is possible for
vitamin B12 deficiency to develop in a much shorter
period of time (months) in some people.
28
Vitamin B12 Deficiency
The vitamin B12 literature contains many articles on the
relative merits and limitations of the various laboratory
testing options. Some tests are used more commonly for
the initial assessment, while others, because of their
cost, inconvenience, or difficulty of interpretation, are
reserved for confirmatory testing in ambivalent
situations or are used only in the research setting.
Initial Assessment
After conducting a thorough history and physical
examination, if you suspect vitamin B12 deficiency, you
should include a complete blood count (CBC), peripheral
blood smear, and serum cobalamin (B12) as part of the
initial laboratory assessment.(58) The serum cobalamin
test is readily available and generally affordable, and can
detect low serum vitamin B12 levels even among patients
who are not anemic.(59, 60) However, not all patients
with a vitamin B12 deficiency will have hematologic
manifestations. As Carmel succinctly noted, вЂњthe
proscription that cobalamin deficiency should not be
diagnosed unless megaloblastic changes are found is
akin to requiring jaundice to diagnose liver disease.вЂќ(11)
While serum vitamin B12 concentrations are generally
accurate,(61) many conditions can complicate the
interpretation of vitamin B12 laboratory values. Falsely
low values have been associated with multiple myeloma,
oral contraceptives,(62-64) folate deficiency,(58, 59)
and pregnancy.(10) Additionally, a low serum B12 level
does not automatically mean a deficiency. From 20%вЂ“
40% of elderly people with low serum B12 levels have
normal metabolite (homocysteine [Hcy] and
methylmalonic acid [MMA]) levels and should not be
considered as having a B12 deficiency.(11)
Sometimes, a true cobalamin deficiency will not be
detected by the serum vitamin B12 test. Some examples
of falsely normal serum cobalamin results might be seen
with (but not limited to) liver disease,(58)
myeloproliferative disorders,(58) and renal
insufficiency.(4, 65) If a patient has clinical evidence of a
vitamin B12 deficiency and a normal serum B12 level, it is
important to evaluate further.
29
The complete blood
count, smear, and serum
cobalamin (B12) test
should be included in the
initial laboratory
assessment of vitamin B12
Oral contraceptive users generally
have lower serum vitamin B12 levels
than nonusers; however, the
evidence of tissue depletion, as
detected by high values of
methylmalonic acid and
homocysteine, is lacking.
вЂњAccepted lower limits of
serum B12 levels in adults
range between 170 and
250 pg/ml; however,
higher levels (but less
than 350 pg/ml) have
been recorded in 15% of
ostensibly healthy elderly
patients with other
findings suggestive of a
deficiency state, most
notably increased levels
of serum methylmalonic
acid. The true lower
limits of normal serum
B12 would therefore
appear to be somewhat
poorly defined.вЂќ
Ward, 2002
Vitamin B12 Deficiency
Opinions differ as to the optimal laboratory cutpoint for
the serum vitamin B12 test, due in part to the insidious
onset and slow progression of the disorder and
limitations of current assays. Research studies and
clinical laboratories have tended to dichotomize low
values at 200 picograms per milliliter(pg/mL).(18, 66,
67) Stabler and Allen noted the following ranges of
serum cobalamin levels among patients with a clinically
confirmed B12 deficiency (defined as those who вЂњhave
objective clinical responses to appropriate therapyвЂќ):
less than 100 pg/mL, approximately 50%; 100вЂ“200
pg/mL, approximately 40%; 200вЂ“350 pg/mL,
approximately 10%; and more than 350 pg/mL,
approximately 0.1% to 1%.(7)
Adequate follow-up for suspect normal or low-normal
results is needed through either additional confirmatory
testing or a prolonged therapeutic trial followed by
metabolic and clinical reassessment.
Confirmatory Testing
When the serum vitamin B12 results are suspect, it is
helpful to obtain more information.(1) Several tests can
be used to rule out a vitamin B12 deficiency either among
patients with borderline serum cobalamin levels or
among symptomatic patients with normal serum
cobalamin levels.
Homocysteine (Hcy) and Methylmalonic Acid (MMA)
By far, the most common, accurate, and widely used
confirmatory tests for identifying vitamin B12 deficiency
are tests for Hcy and MMA.(1) Because cobalamin is
necessary for the synthesis of methionine from Hcy, low
levels of vitamin B12 lead to increases in total serum
Hcy. The total serum Hcy test is a sensitive indicator for
a vitamin B12 deficiency; however, its utility is limited as
a sole confirmatory test because elevated Hcy levels
among patients also can be caused by familial
hyperhomocysteinemia, levodopa therapy,(68) renal
insufficiency, and folate deficiency.(1, 7, 69, 70)
The serum MMA test is more specific for vitamin B12
deficiency than the Hcy test.(1, 2, 7, 69, 70) MMA levels
also increase in the presence of low vitamin B12 levels
30
Vitamin B12 Deficiency
because cobalamin is required to convert methylmalonyl
coenzyme A to succinyl coenzyme A.(2) In one study,
98.4% of people with a vitamin B12 level less than 200
pg/mL also had elevated MMA levels (defined as values
more than 376 nanomoles per liter [nmol/L]).(70) Note
that false-positive increases in serum MMA have been
identified among patients with impaired renal function. It
is necessary to rule out whether your patient has either
marked intravascular volume depletion or renal
insufficiency when interpreting the MMA level, especially
in the absence of a low cobalamin level.(70) Elevated
MMA levels among most patients indicate tissue
depletion of vitamin B12. Data from the National Health
and Nutrition Examination Survey (NHANES) 2001вЂ“2004
in Table 4 shows the prevalence of vitamin B12 deficiency
using combinations of serum B12 levels and MMA levels.
Table 4. Prevalence of National Health and Nutrition
Examination Survery Participants With Biochemically
Defined Vitamin B12 Deficiency* By Age Group, United
States, 2001вЂ“2004
Age Group
(Years of Age)
B12 в‰¤ 200
pg/mL and MMA
в‰Ґ 270 nmol/L
B12 > 200 pg/mL
and MMA в‰Ґ 270
nmol/L
9вЂ“13 years of age
0.1%
2.5%
14вЂ“18 years of age
0.2%
3.7%
19вЂ“30 years of age
0.4%
3.5%
31вЂ“50 years of age
0.6%
3.6%
в‰Ґ 51 years of age
1.6%
7.9%
Conversions
*Biochemically defined vitamin B12 deficiency is serum B12 в‰¤ 200
picograms per milliliter (pg/mL) and methylmalonic acid (MMA) в‰Ґ
270 nanomoles per liter (nmol/L) or serum B12 > 200 pg/mL and
MMA в‰Ґ 270 nmol/L
1,000 nmol/L* = 1
Вµmol/LвЂ 376 nmol/L = 0.376
Two popular methods for interpreting diagnostic
thresholds for MMA and Hcy elevations are the use of
cutpoints determined by laboratory norms (e.g., 3
standard deviations above the mean) and specific values
(e.g., MMA greater than 0.26 micromole per liter
31
*nanomols per liter
вЂ micromols per liter
Вµmol/L
Vitamin B12 Deficiency
[Вµmol/L](69) or greater than 0.4 Вµmol/L;(59) Hcy
greater than 15 Вµmol/L(71, 72)). Many clinicians rely on
ranges specified by the clinical laboratories they use.
The cost of testing for MMA or Hcy might be a concern.
Quotes from Quest Laboratories (Atlanta, Georgia, May
2006) state that the direct patient (no insurance) cost
for a serum MMA is $212 and for a serum Hcy is $191.
Other metabolites, serum propionate and serum 2methylcitrate, are also present in vitamin B12 deficiency.
However, measuring either of these metabolites has no
advantage over measuring MMA to diagnose a vitamin
B12 deficiency,(2) and they are not available routinely in
many clinical laboratories.
Again, it is important to remember that abnormal
metabolite levels might be due to conditions other than
a vitamin B12 deficiency, such as renal insufficiency. In
one study of the elderly, renal insufficiency was
associated with 20% or greater of all abnormal
metabolite levels.(11)
Other Tests
If the root cause of vitamin B12 deficiency is not obvious,
you should consider ordering additional tests to
determine it. Antibodies to intrinsic factor and gastrin or
pentagastrin I levels are often used to diagnose
pernicious anemia.(10, 36, 60)
Serum holotranscobalamin II measures one of the bloodbinding proteins used to transport vitamin B12.(60) Some
investigators recommend it;(73) others are concerned
about the lack of convincing evidence of its value.(2, 9,
10, 60) Theoretically, it is attractive, but early claims of
its value have been poorly documented. While
immunoassays have replaced the older crude methods, it
is too early to determine whether measurement of
holotranscobalamin II is better than measurement of
serum cobalamin. (1)
The deoxyuridine suppression test ( or вЂњDUSTвЂќ) has been
described as a sensitive indicator of impaired thymidine
synthesis due to either deficiency or metabolic
inactivation of vitamin B12 or folate.(58) However, DUST
32
Vitamin B12 Deficiency
is used rarely in the clinical setting because it is not
necessary in the evaluation of a vitamin B12 deficiency.
DUST is also a complicated, expensive, and timeconsuming test.(58)
The Schilling test is included in most lists of possible
vitamin B12 deficiency confirmatory tests, but it is not
available in U.S. clinical practices at this time. The
Shilling test is the classic test for determining whether a
person can absorb vitamin B12. However, a personвЂ™s
ability to absorb crystalline vitamin B12 can differ from
his or her ability to absorb the naturally occurring
vitamin B12.(59) While, it is not an accurate test for
identifying cobalamin deficiency, it can be a helpful tool
in determining the root cause of an identified deficiency.
It reveals cobalamin malabsorption such as that found in
pernicious anemia and ileal disease. A normal Schilling
test cannot rule out vitamin B12 deficiency.(29, 36)
There is no gold standard for determining cobalamin
deficiency. Part of the problem is related not to the tests
used, but to вЂњan uncertain boundary between cobalamin
depletion and disease.вЂќ(1, 20)
A diagnostic approach to tailor testing to the nature of a
patientвЂ™s clinical problem is suggested by Carmel and
summarized in Table 5(1)
33
Vitamin B12 Deficiency
Table 5. Tailored Diagnostic Approach
Vitamin B12 Deficiency
Problem
Goal
Patient with mild to Confirm suspected
severe hematologic vitamin B12
or neurologic signs deficiency
or symptoms, or
both
Patient with
Ensure if vitamin
hematologic or
B12 deficiency
neurologic signs or exists, it is not
missed
symptoms, or
both, unlikely due
to vitamin B12
deficiency
Asymptomatic
Determine if
patient with
vitamin B12
condition known to deficiency has
cause vitamin B12
developed yet
deficiency
Determine if
Asymptomatic
patient accidentally vitamin B12
deficiency exists
found to have low
B12 level or high
HcyвЂ for
Suggested Tests
Serum B12
Serum B12
MMA* and HcyвЂ MMA (metabolic
changes often
precede low
cobalamin levels)
MMA
*MMAвЂ“methylmalonic acid
вЂ HcyвЂ“homocysteine
Flagging the patientвЂ™s chart will help you remember to
follow-up if choosing to вЂњwatch and waitвЂќ with an
asymptomatic patient.
Experienced clinicians differ on the importance of
tracking down the root cause of a vitamin B12 deficiency
before initiating treatment; however, determining the
cause of the deficiency is important ultimately in
individualizing the treatment approach.(1)
34
Vitamin B12 Deficiency
Managing Patients With Evidence of a
Vitamin B12 Deficiency
вЂњA caregiver must manage a subclinically deficient
patient with pernicious anemia as a cause quite
differently and pay closer attention than to a similar
patient without it.вЂќ
Carmel, 2006
Clinical Vitamin B12 Deficiency
Options available for treating a clinical vitamin B12
deficiency include oral and parenteral (intramuscular or
subcutaneous) preparations. Intravenous dosing is not
recommended because this will result in most of the
vitamin being lost in the urine.(74)
The response of a patient with vitamin B12 deficiency
anemia to treatment is usually rapid, with reticulocytosis
occurring within 2вЂ“5 days, and the hematocrit
normalizing within weeks.(10) Treatment with cobalamin
effectively halts progression of the deficiency process,
but might not fully reverse more advanced neurologic
effects.(39, 42) If the underlying cause of the vitamin
B12 deficiency is treatable (e.g., fish tapeworm infection
or bacterial overgrowth), then treatment should include
addressing the underlying etiology.(7)
Vitamin B12 is considered safe, even at levels much
higher than the recommended dose. It has not been
shown to be toxic or cause cancer, birth defects, or
mutations.(10, 75) Be aware, however, that patients
who have a vitamin B12 deficiency with associated
megaloblastic anemia might experience hypokalemia and
fluid overload early in treatment due to increased
erythropoiesis, cellular uptake of potassium, and
increased blood volume.(76, 77)
While the route, dosage, treatment timing, and follow-up
might vary somewhat, there is no question about the
decision to treat patients with pernicious anemia or with
a low serum B12 level and hematologic or neurologic
signs or symptoms without pernicious anemia (clinical
35
Cobalamin replacement is
effective because
crystalline forms of B12 can
be absorbed even when
animal protein-bound
forms cannot be digested.
Vitamin B12 is not
carcinogenic, teratogenic,
or mutagenic. It is
considered safe even at
1,000 times the RDA.
Baik and Russell, 1999
Vitamin B12 Deficiency
vitamin B12 deficiency). Once treated for a vitamin
B12 deficiency due to pernicious anemia or other
irreversible severe problems with absorption,
patients need to continue some form of cobalamin
therapy for life.(7)
Parenteral (Intramuscular or Subcutaneous)
Administration of parenteral crystalline cobalamin has
been the standard treatment protocol for vitamin B12
deficiency for decades.(78, 79) Few side effects have
been reported, and patient acceptance is generally high.
Anecdotally, the subcutaneous route causes less burning
than does the intramuscular route (Carmel RA. New York
Methodist Hospital [personal communication] 20062007). Regimens for parenteral administration vary. An
approach suggested by Stabler and Allen is 1
milligram (mg) (or 1,000 micrograms [Вµg]) of
vitamin B12 given weekly for 8 weeks, then once
monthly for life.(7)
Some providers have used quarterly injections after the
initial dosing protocol. However, experts state that in
pernicious anemia or severe malabsorptive deficiency
quarterly injections are not sufficient, noting that
cobalamin levels start to fall prior to the 1 month followup (Allen RH. University of Colorado [personal
communication] 2006 -2007).
Oral
Large, daily oral replacement doses might be an
acceptable alternative if patients are compliant.(7)
Sufficient amounts of vitamin B12 are absorbed via
passive diffusion in the small intestine.(2, 11) A study by
Eussen et al. demonstrated a linear response in the
reduction of metabolites and increased serum B12 levels
with increasing dosages of oral cyanocobalamin.(80) A
common therapy is 1 mg (1,000 Вµg) of vitamin B12
to be consumed daily.(2, 11, 14)
Intranasal
A relatively new vehicle for vitamin B12 therapy is a
cyanocobalamin gel for intranasal use. Some experts
are not convinced of its efficacy, and the cost is $30 for
36
Vitamin B12 Deficiency
500 Вµg (Carmel RA. New York Methodist Hospital
[personal communication] 2006-2007). If chosen, the
intranasal gel should be used for maintenance only after
treatment with parenteral or oral vitamin therapy has
established adequate metabolic status among patients
with no nervous system involvement.(74) The
recommended dose for therapy is 500 Вµg
intranasally once a week.(74) Absorption can be
inconsistent.
Treatment approaches vary somewhat in the initial
treatment and the route used.(7, 77, 81) Given the
long-term nature of cobalamin therapy, consideration of
the patientвЂ™s condition (e.g., cognitive impairment),
convenience of getting the treatment, and ease of
administration should heavily influence the method and
dosage selected.(7, 11) For example, oral therapy is less
painful and can be self-administered. However, because
cognitive impairment is a frequent reason for
noncompliance, patients might be more compliant with
clinic or home health nurse-administered injections.
Additionally, Carmel observed that many patients prefer
the convenience of monthly injections to daily
consumption of pills.(11)
Examples of treatment regimens from different sources
for clinical vitamin B12 deficiency are listed in Table 6.
37
Vitamin B12 Deficiency
Table 6. Examples of Treatment Regimens
for Clinical Vitamin B12 Deficiency
Due to
Initial
Cyanocobalamin
Pernicious
Varies, not limited
anemia
to:
п‚· 1 mg
intramuscularly
(IM) or
subcutaneously
(SQ) every (q)
week x 8
OR
п‚· 1 mg IM or SQ x
7 in 1 month
Other foodVaries, not limited
to:
bound B12
malabsorption п‚· 1 mg IM or SQ q
problems
week x 8
OR
п‚· 1 mg IM or SQ x
7 in 1 month
OR
п‚· 1 mgвЂ“2 mg PO
QD
Rarer
п‚· Treat underlying
malabsorption
condition
problems
AND
(tape worms, Cyanocobalamin
bacterial
varies, not limited
overgrowth)
to:
п‚· 1 mg IM or SQ q
week x 8
OR
п‚· 1 mg IM or SQ x
7 in 1 month
Maintenance
Cyanocobalamin
п‚· 1 mg IM or SQ q
month for life
OR
п‚· 1 mgвЂ“2 mg
orally (PO)
every day (QD)
for life
п‚·
1 mg IM or SQ q
month possibly
for life
OR
п‚· 650 ВµgвЂ“1 mg PO
QD possibly for
life
п‚·
1 mg IM or SQ q
month
OR
п‚· 650 ВµgвЂ“1 mg PO
QD
Treating underlying
condition might
resolve B12
deficiency. If
cyanocobalamin is
d/cвЂ™d, follow up
with regular
assessment of
metabolites.
38
Vitamin B12 Deficiency
Subclinical Vitamin B12 Deficiency
The far more prevalent patient presentation is by an
asymptomatic individual with borderline serum B12 levels
and elevated homocysteine or methylmalonic acid levels,
or both. These patients pose a dilemma for providers
because there are no guidelines for the treatment of
patients with subclinical vitamin B12 deficiency.
Some providers prefer to treat these patients and check
to see that metabolite markers have normalized, while
others prefer to вЂњwait and watchвЂќ. For patients in the
subclinical vitamin B12 deficiency category, taking a
vitamin with B12 (usual dosages are 6вЂ“25 Вµg) is not
sufficient to correct the metabolites. Two recent studies
have suggested that the lowest dose of oral
cyanocobalamin needed to normalize metabolites in
subclinical vitamin B12 deficiency is 500вЂ“1,000 Вµg
daily.(80, 82) The providers who test for and treat
patients with subclinical vitamin B12 deficiency, especially
those patients with possible pernicious anemia or
elevated metabolites, or both, can prevent potential
subsequent hematologic and neurologic manifestations.
Whether treating or вЂњwaiting and watchingвЂќ, you should
remember that routine monitoring of and educating the
patient are important.
39
Vitamin B12 Deficiency
Prevention of Vitamin B12 Deficiencies
вЂњThe . . . Recommended Dietary Allowance (RDA) (2.4
mcg/day) for B12 for adults ages 51 and older are the
same as for younger adults but with the
recommendation that B12вЂ“fortified foods (such as
fortified ready-to-eat cereals) or B12вЂ“containing
supplements be used to meet much of the
requirements.вЂќ Institute of Medicine, 1999
The irreversible nature of the late-stage neurologic
effects of a vitamin B12 deficiency provides strong
support for the value of prevention.(44, 50, 83)
Fortunately, a vitamin B12 deficiency is easily treated and
prevented. Because of the high prevalence of mild,
subclinical cobalamin deficiency among asymptomatic
individuals, it is important to remain vigilant, especially
with individuals at high risk for a vitamin B12 deficiency.
If вЂњwatch and waitвЂќ is the selected plan of care, periodic
reassessment of untreated asymptomatic patients is
important to identify progressive depletion of vitamin
B12.
The Institute of Medicine (IOM) recommends that all
adults 18 years of age or older consume 2.4 micrograms
(Вµg) per day of vitamin B12.(10) Subclinical vitamin B12
deficiency, often undiagnosed and untreated, has been
estimated to occur among 5%вЂ“15% of the elderly
population.(4, 6, 16, 19, 65) However, a recent clinical
study demonstrates that it takes 650вЂ“1,000 Вµg of
cyanocobalamin daily to provide 80%вЂ“90% of the
estimated maximum reduction in methylmalonic
acid.(80)
Given the high prevalence of atrophic gastritis (loss of
acid secretion) among older adults, the IOM suggests
that adults older than 50 years of age use vitamin B12вЂ“
fortified foods and supplements (e.g., multivitamins or
single supplements) as the primary means to meet this
requirement because crystalline formulations are much
more readily absorbed and used than naturally occurring
vitamin B12. Most multivitamins contain 6вЂ“25 Вµg
cyanocobalamin; some contain more. Single
40
The irreversible nature of
the late-stage neurologic
effects of a vitamin B12
deficiency provides
strong support for the
value of prevention.
Vitamin B12 Deficiency
supplements typically come in doses of 100 Вµg, 250 Вµg,
500 Вµg, 1,000 Вµg, and 2,000 Вµg. For more information
on vitamin supplements for adults, see the National
Institutes of Health Office of Dietary Supplements
website at
http://ods.od.nih.gov/factsheets/cc/vitb12.html.
Vegans, or strict vegetarians, must obtain their per-day
dose of vitamin B12 by consuming a vitamin supplement
or eating a fortified cereal product. Currently available
data do not support the suggestion that vegans can
meet their minimum daily requirements for vitamin B12
by consuming unfortified plant-based foods, nutritional
yeast, algae, or seaweed products.
For more information on the vitamin B12 levels of over
1,100 common food items, visit the U.S. Department of
Agriculture and Agricultural Research website at
http://www.ars.usda.gov/ba/bhnrc/ndl.
Several experts in the field find that even higher doses
of oral cobalamin are necessary for the prevention of
vitamin B12 deficiency among the elderly and have stated
that the amount in the IOM recommendation is
insufficient.(80)(Carmel RA. New York Methodist Hospital
[personal communication] 2006-2007; Allen RH.
University of Colorado [personal communication] 20062007) LindenbaumвЂ™s findings of the prevalence of
cobalamin deficiency among the elderly survivors from
the Framingham study suggests вЂњdeficiencies can, at
least in part, be prevented by oral supplementation,
although . . . the dose of cobalamin administered may
have to be much larger than that usually given in routine
multivitamin preparations.вЂќ(4)
41
Vitamin B12 Deficiency
Summary
Low vitamin B12 levels occur among 1 in 31 adults 51
years of age or older among the U.S. population. Vitamin
B12 deficiency is simple to prevent and simple to treat,
but the diagnosis is easy to miss and is often overlooked
in the outpatient setting.
All patients with unexplained hematologic or neurologic
symptoms should be evaluated for a vitamin B12
deficiency. If such a deficiency is found, the cause
should be determined.(7, 44) Irreversible neurologic
damage can occur if diagnosis and treatment are
delayed.
A complete blood count, peripheral blood smear, and
serum vitamin B12 level are the tests of choice for initial
assessment of cobalamin deficiency. Keep in mind that
megaloblastic anemia and changes in mean corpuscular
value are not always present when there is a vitamin B12
deficiency. Homcysteine and methylmalonic acid can be
used to confirm a vitamin B12 deficiency for cases with
ambiguous initial results because metabolic changes
often precede low cobalamin levels.
You have inexpensive treatment options available to
treat a vitamin B12 deficiency. Remember that treatment
is safe, effective, and has no known toxicity level.
To prevent a vitamin B12 deficiency, you should advise
all patients 51 years of age or older to consume
synthetic vitamin B12 daily. Dosage recommendations
vary.
Acknowledgements: The authors thank Christine Pfeiffer, PhD, for
assistance with laboratory interpretation, and Quanhe Yang,
PhD,and Heather Carter Hamner, MS, MPH, for statistical support.
We also appreciate the comments and suggestions from our panel
of reviewers Sonja Rasmussen, MD; Joe Mulinare, MD; R.J. Berry,
MD; Lorraine Yeung, MD; Sharon Roy, MD; Mary Dott, MD; John
Mersereau, MD; Jennifer Zreloff, MD; Jason Bell, MD; Pauline
Terebuh, MD; Dan Watkins, PA; Gail Walls, MSN; Sally Lehr, MSN;
Darla Ura, MSN; Sue Ann Bell, MSN; Christa Purnell, MSN; Molly
Cogswell, RN, PhD, and Malissa Perritt, MSN.
42
Vitamin B12 Deficiency
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Whyte EM, Mulsant BH, Butters MA, Qayyum M, Towers
A, Sweet RA, et al. Cognitive and behavioral correlates of low
vitamin B12 levels in elderly patients with progressive
dementia. Am J Geriatr Psychiatry. 2002 May-Jun;10(3):3217.
67.
Stabler SP. Screening the older population for
cobalamin (vitamin B12) deficiency. J Am Geriatr Soc. 1995
Nov;43(11):1290-7.
68.
O'Suilleabhain PE, Sung V, Hernandez C, Lacritz L,
Dewey RB, Jr., Bottiglieri T, et al. Elevated plasma
homocysteine level in patients with Parkinson disease: motor,
affective, and cognitive associations. Arch Neurol. 2004
Jun;61(6):865-8.
69.
Bolann BJ, Solli JD, Schneede J, Grottum KA, Loraas A,
Stokkeland M, et al. Evaluation of indicators of cobalamin
deficiency defined as cobalamin-induced reduction in
increased serum methylmalonic acid. Clin Chem. 2000
Nov;46(11):1744-50.
70.
Savage DG, Lindenbaum J, Stabler SP, Allen RH.
Sensitivity of serum methylmalonic acid and total
homocysteine determinations for diagnosing cobalamin and
folate deficiencies. Am J Med. 1994 Mar;96(3):239-46.
47
Vitamin B12 Deficiency
71.
Ray JG, Cole DE, Boss SC. An Ontario-wide study of
vitamin B12, serum folate, and red cell folate levels in relation
to plasma homocysteine: is a preventable public health issue
on the rise? Clin Biochem. 2000 Jul;33(5):337-43.
72.
Holleland G, Schneede J, Ueland PM, Lund PK, Refsum
H, Sandberg S. Cobalamin deficiency in general practice.
Assessment of the diagnostic utility and cost-benefit analysis
of methylmalonic acid determination in relation to current
diagnostic strategies. Clin Chem. 1999 Feb;45(2):189-98.
73.
Herbert V. The elderly need oral vitamin B-12. Am J
Clin Nutr. 1998 Apr;67(4):739-40.
74.
RXList I. Cyanocobalamin. WebMD; 2008.
75.
Schauss AG. Recommended optimum nutrient intakes.
In: Pizzorno, editor. Textbook of Natural Medicine. 2nd ed:
Churchill Livingstone, Inc.; 1999. p. 909-27.
76.
Hoffman R, Benz E, Shattil S, Furie B, Cohen H,
Silberstein L, et al. Hematology: Basic Principles and Practice.
4th ed. Philadelphia: Elsevier Churchill Livingstone; 2005.
77.
Marks PW, Zukerberg LR. Case records of the
Massachusetts General Hospital. Weekly clinicopathological
exercises. Case 30-2004. A 37-year-old woman with
paresthesias of the arms and legs. N Engl J Med. 2004 Sep
23;351(13):1333-41.
78.
Lawhorne LW, Wright H, Cragen D. Characteristics of
non-cobalamin deficient patients who receive regular
cyanocobalamin injections. Fam Med. 1991 SepOct;23(7):506-9.
79.
Hughes D, Elwood PC, Shinton NK, Wrighton RJ. Clinical
trial of the effect of vitamin B12 in elderly subjects with low
serum B12 levels. Br Med Journal. 1970;2:458-60.
80.
Eussen SJ, de Groot LC, Clarke R, Schneede J, Ueland
PM, Hoefnagels WH, et al. Oral cyanocobalamin
supplementation in older people with vitamin B12 deficiency:
a dose-finding trial. Arch Intern Med. 2005 May
23;165(10):1167-72.
81.
Solomon LR. Cobalamin-responsive disorders in the
ambulatory care setting: unreliability of cobalamin,
methylmalonic acid, and homocysteine testing. Blood. 2005
Feb 1;105(3):978-85.
82.
Stabler SP, Allen RH, Dolce ET, Johnson MA. Elevated
serum S-adenosylhomocysteine in cobalamin-deficient elderly
and response to treatment. Am J Clin Nutr. 2006
Dec;84(6):1422-9.
83.
Wolters M, Strohle A, Hahn A. Cobalamin: a critical
vitamin in the elderly. Prev Med. 2004 Dec;39(6):1256-66.
48
Vitamin B12 Deficiency
References for Text in Boxes
Amos R, Dawson D, Fish D, Leeming R, Linnell J.
Guidelines on the investigation and diagnosis of
cobalamin and folate deficiencies. A publication of the
British Committee for Standards in Haematology. BCSH
General Haematology Test Force. Clin Lab Haematol.
1994 Jun;16(2):101вЂ“15.
Baik H, Russell R. Vitamin B12 deficiency in the elderly.
Annual Rev Nutr.1999(19):357вЂ“77.
Bernard MA, Nakonezny PA, Kashner TM. The effect of
vitamin B12 deficiency on older veterans and its
relationship to health. J Am Geriatr Soc. 1998
Oct;46(10):1199вЂ“206.
Carmel R. Current concepts in cobalamin deficiency.
Annu Rev Med. 2000;51:357вЂ“75.
Carmel R, Green R, Rosenblatt DS, Watkins D. Update
on cobalamin, folate, and homocysteine. Hematology
(Am Soc Hematol Educ Program). 2003:62вЂ“81.
U.S. Food and Drug Administration (FDA). Food
standards: amendment of standards of identity for
enriched grain products to require addition of folic acid. .
Fed Regist, 1996; 61(44): 8781-97.
Herbert V. Staging vitamin B-12 (cobalamin) status in
vegetarians. Am J Clin Nutr. 1994 May;59(5
Suppl):1213SвЂ“22S.
Institute of Medicine (IOM). Dietary reference intakes for
thiamin, riboflavin, niacin, vitamin B6, folate, vitamin
B12, pantothenic acid, biotin and choline. Washington,
D.C.: National Academy Press; 1998.
Matchar DB, McCrory DC, Millington DS, Feussner JR.
Performance of the serum cobalamin assay for diagnosis
of cobalamin deficiency. Am J Med Sci. 1994
Nov;308(5):276вЂ“83.
49
Vitamin B12 Deficiency
Pennypacker LC, Allen RH, Kelly JP, Matthews LM,
Grigsby J, Kaye K, et al. High prevalence of cobalamin
deficiency in elderly outpatients. J Am Geriatr Soc. 1992
Dec;40(12):1197вЂ“204.
Rajan S, Wallace JI, Beresford SA, Brodkin KI, Allen RA,
Stabler SP. Screening for cobalamin deficiency in
geriatric outpatients: prevalence and influence of
synthetic cobalamin intake. J Am Geriatr Soc. 2002
Apr;50(4):624вЂ“30.
Stabler SP, Allen RH. Megoblastic anemias. In: Goldman,
ed. Cecil Textbook of Medicine, 22nd ed. Philadelphia:
W. B. Saunders Company; 2004. p. 1050вЂ“7.
Ward PC. Modern approaches to the investigation of
vitamin B12 deficiency. Clin Lab Med. 2002
Jun;22(2):435вЂ“45.
50
Vitamin B12 Deficiency
Appendix A
Answers to Case Study Questions
1.
Do any of the presenting complaints raise
your index of suspicion about a possible
vitamin B12 deficiency? If so, why? Yes.
Complaints of tiredness for 2 months and memory
problems in a woman 65 years of age might
indicate a vitamin B12 deficiency.
2.
What risk factors does this woman appear to
have for a vitamin B12 deficiency? The only
immediately apparent risk factor is her age. Risk
of developing a deficiency begins to increase at 51
years of age. Sex is not an important predictor.
The patientвЂ™s nutritional status is unclear at this
stage. Future questions might usefully probe the
patient for regular sources of vitamin B12, including
meat and dairy products as well as fortified foods
and nutritional supplements.
3.
Does the fact that she appears to be вЂњwellnourishedвЂќ indicate she is unlikely to have a
vitamin deficiency? Why or why not? No. The
fact that she is well-nourished does not rule out a
potential deficiency. Weight, or body mass index,
is not a useful predictor. Normal and overweight
individuals might still have a significant vitamin B12
deficiency because most deficiencies are due to
malabsorption rather than malnutrition. Markedly
underweight patients, who might truly be
malnourished, are at increased risk for a vitamin
B12 deficiency, particularly if they are elderly or
have been adhering to a vegetarian or vegan diet
for several years.
4.
Are there any aspects of her physical
examination that suggest a vitamin B12
deficiency? Mucosal and skin pallor are subtle
signs.
51
Vitamin B12 Deficiency
5.
Given her history and physical examination
findings, what laboratory test(s) would you
order? In addition to the usual chemistry panel
and complete blood count with smear to check for
anemia, a serum B12 test should be ordered. Lownormal levels indicate a need for further
assessment because serum levels can be
maintained at the expense of liver stores even in
the presence of ongoing malabsorption.
52
Vitamin B12 Deficiency
Appendix B
Additional Articles on Vitamin B12
Deficiency
Allen R, Lindenbaum J, Stabler S. High prevalence
of cobalamin deficiency in the elderly. Trans Am
Clin Climatol Assoc. 1995;107:37вЂ“45.
Carmel R, Melnyk S, James J. Cobalamin deficiency
with and without neurologic abnormalities:
differences in homocysteine and methionine
metabolism. Blood. 2003;101:3302вЂ“8.
Carmel R. Pernicious anemia: the expected
findings of very low cobalamin levels, anemia, and
macrocytosis are often lacking. Arch Intern Med.
1988;148:1712вЂ“4.
Clarke R. Prevention of vitamin B-12 deficiency in
old age. Am J Clin Nutr. 2001;73:151вЂ“2.
Fairfield K, Fletcher R. Vitamins for chronic disease
prevention in adults - Scientific Review. JAMA.
2002;287:3116вЂ“26.
Fletcher R, Fairfield K. Vitamins for chronic disease
prevention in adults - clinical applications. JAMA.
2002;287:3127вЂ“9.
Herbert V. Vitamin B12 and folic acid
supplementation. Am J Clin Nutr. 1997;66:1479вЂ“
80.
Herrmann W, Schorr H, Bodis M, Knaapp J, Muller
A, Stein G, et al. Role of homocysteine,
cystathionine and methylmalonic acid
measurement for the diagnosis of vitamin
deficiency in high-aged subjects. Eur J Clin Invest.
2000;30:1083вЂ“9.
Ho G, Kauwell G, Bailey L. PractitionersвЂ™ guide to
meeting the vitamin B12 recommended dietary
allowances for people aged 51 years and older. J
Am Diet Assoc. 1999;99:725вЂ“7.
53
Vitamin B12 Deficiency
Holleland G, Schneede J, Ueland P, Lund P, Refsum
H, Sandberg S, et al. Cobalamin deficiency in
general practice: assessment of the diagnostic
utility and cost-benefit analysis of methylmalonic
acid determination in relation to current diagnostic
strategies. Clin Chem. 1999;45:189вЂ“98.
Hvas A, Ellegaard J, Nexo E. Increased plasma
methylmalonic acid level does not predict clinical
manifestations of vitamin B12 deficiency. Arch
Intern Med. 2001;161:1535вЂ“41.
Johnson M, Hawthorne N, Brackett W, Fischer J,
Gunter E, Allen R, et al. Hyperhomocysteinemia
and vitamin B12 deficiency in elderly using title
IIIC nutrition services. Am J Clin Nutr.
2003;77:211вЂ“20.
Lokk J, Nilsson M, Norberg B, Hultdin J, Sandstrom
H, Westman G. Shifts in B12 opinions in primary
health care of Sweden. Scand J Public Health.
2001;29:122вЂ“8.
Malouf R, Areosa S. Vitamin B12 for cognition.
Cochrane Database Syst Rev. 2003:3.
Meins W, Muller-Thomsen T, Meier-Baumgartner
H. Subnormal serum vitamin B12 and behavioral
and psychological symptoms in AlzheimerвЂ™s
disease. Int J Geriatr Psychiatry. 2000;15:415вЂ“8.
Misra U, Kalita J, Das A. Vitamin B12 deficiency
neurological syndromes: a clinical, MRI, and
electrodiagnostic study. Electromyogr Clin
Neurophysiol. 2003;43:57вЂ“64.
Mitchell S, Rockwood K. The association between
antiulcer medication and initiation of cobalamin
replacement in older persons. J Clin Epidemiol.
2001;54:531вЂ“4.
Naurath H, Joosten E, Riezler R, Stabler S, Allen R,
Lindenbaum J. Effects of vitamin B12, folate, and
vitamin B6 supplements in elderly people with
normal serum vitamin concentrations. Lancet.
1995;346:85вЂ“9.
54
Vitamin B12 Deficiency
Penninx BW, Guralnick JM, Ferrucci L. Fried LP,
Allen R, Stabler S. Vitamin B(12) deficiency and
depression in physically disabled older women:
epidemiologic evidence from the WomenвЂ™s Health
and Aging Study. Am J Psychiatry.
2000;157:715вЂ“21.
Stopeck A. Links between helicobacter pylori
infection, cobalamin deficiency, and pernicious
anemia. Arch Intern Med. 2000;160:1229вЂ“30.
Tiemeier H, van Tuiji H, Hoffman A, Meijer J,
Kilaan A, Breteler M. Vitamin B12, folate, and
homocysteine in depression: the Rotterdam Study.
Am J Psychiatry. 2002;159:2099вЂ“101.
van Asselt D, Blom H, Zuiderent R, Wevers R,
Jakobs C, van den Broek W, et al. Clinical
significance of low cobalamin levels in older
hospital patients. Neth J Med. 2000;57:41вЂ“9.
55
Vitamin B12 Deficiency
Appendix C
Why Vitamin B12 Deficiency Should Be
on Your Radar Screen
Evaluation Questionnaire and
Posttest
Course Goal: To increase the number of primary care
providers (physicians and midlevel providers) who
prevent, detect, and treat vitamin B12 deficiencies
among their high-risk patients.
Objectives:
вЂў
вЂў
вЂў
вЂў
вЂў
вЂў
Describe the prevalence in the United States of
vitamin B12 deficiency among adults 51 years of
age or older.
List three neurologic effects of a vitamin B12
deficiency.
List three hematologic effects of a vitamin B12
deficiency.
Identify the most common presentation of a
vitamin B12 deficiency.
Discuss the changes in absorption of vitamin B12
that occur with age.
List at least two pharmacologic options for
treatment of a vitamin B12 deficiency.
1. The learning outcomes (objectives) were relevant to
the goal of this course.
a. Strongly agree
b.Agree
c. Undecided
d. Disagree
e. Strongly disagree
2. The content was appropriate given the stated
objectives of the course.
a. Strongly agree
b. Agree
56
Vitamin B12 Deficiency
c. Undecided
d. Disagree
e. Strongly disagree
3. The content was presented clearly.
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
4. The learning environment was conducive to learning.
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
5. The delivery method (i.e., Web) helped me learn the
material more easily.
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
6. The instructional strategies helped me learn the
material.
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
7. Overall, the quality of the course materials was
excellent.
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
8. The course was
a. Much too difficult
b. A little too difficult
c. Just right
57
Vitamin B12 Deficiency
d. A little too easy
e. Much too easy
9. Overall, the course was
a. Much too long
b. A little too long
c. Just right
d. A little too short
e. Much too short
10. The availability of continuing education credit
influenced my decision to participate in this activity.
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
f. Not applicable
11. As a result of my completing this educational
activity, it is likely that I will make changes in my
practice.
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
f. Not applicable
12. I am confident I can describe the prevalence in the
United States of vitamin B12 deficiency among adults 51
years of age or older.
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
13. I am confident I can list three neurologic effects of a
vitamin B12 deficiency.
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
58
Vitamin B12 Deficiency
14. I am confident I can list three hematologic effects of
a vitamin B12 deficiency.
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
15. I am confident that I can identify the most common
presentation of vitamin B12 deficiency.
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
16. I am confident that I can discuss the changes in
absorption of vitamin B12 that occur with age.
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
17. I am confident I can list at least two pharmacologic
options for treatment of a vitamin B12 deficiency.
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
18. The content expert(s) for this document
demonstrated expertise in the subject matter.
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
19. Do you feel this course was commercially biased?
Yes or No
If yes, please explain
59
Vitamin B12 Deficiency
20. Please describe in the following space any technical
difficulties you experienced with the course.
21. What could be done to improve future course
offerings?
22. Do you have any further comments?
60
Vitamin B12 Deficiency
Pretest and Posttest
If you want to receive continuing education credit for
this program, complete this posttest. Please read the
case history and then answer the questions that follow.
Choose the answer that is most correct for each
question.
Case
A 60-year-old teacher with a history of hypothyroidism
and gastroesophageal reflux disease (GERD) reports
significant fatigue, hot flashes, and memory difficulty
since her last annual visit. On detailed review of
symptoms, she also admits to irritability, emotional
lability, decreased appetite, difficulty sleeping, and
occasional tingling of her fingertips. Her last monthly
period was 2 years ago. She has been following a
vegetarian diet for the past 5 years to try to lose weight.
During the physical examination, she is alert and
oriented x 3, but tearful at one point during the
interview with an MMSE score of 28 out of 30. There are
no abnormal physical findings.
Her CBC results:
RBC 4.6 (4.2вЂ“5.8) 10^6/ВµL
MCV 90
(78вЂ“102) fL
Hgb 15
(12.0вЂ“16.0)
g/dL
WBC 6.4 (4.3вЂ“11.0) 10^3/ВµL (normal differential)
Plts 312 (144вЂ“440) 10^3/ВµL
Smear shows normocytic, normochromic RBCs
Chemistry results:
Na
139 (136вЂ“148) mEq/L
K
4.7 (3.5вЂ“5.5) mEq/L
Cl
103 (98вЂ“110) mmol/L
BUN 20.0 (9.34вЂ“23.35)mg/dL
Cr
1.0 (0.4вЂ“1.5) mg/dL
(21вЂ“33)
mmol/L
CO2 25
Gluc 80
(60вЂ“140) mg/dL
GOT 26
(1вЂ“32)
U/L
GPT 14
(1вЂ“30)
U/L
AlkPhos 115 (31вЂ“121) U/L
61
Vitamin B12 Deficiency
1.
Which of the following presenting symptoms
suggest this patient might have a vitamin B12
deficiency?
a. Fatigue
b. Difficulty sleeping
c. Hot flashes
d. Emotional lability
e. All of the above
2.
All of the following factors might place this
patient at high risk for a vitamin B12 deficiency
except:
a. Being 51 years of age or older
b. Being female sex
c. Having hypothyroidism
d. Following a vegetarian diet
3.
You might find ______ patients with evidence
of low vitamin B12 levels in every 100 patients
you see. (Hint: Use prevalence data from the
research literature to determine your answer.)
a. 0вЂ“1
b. 2вЂ“4
c. 8вЂ“10
d. 15 or more
4.
What can you conclude from the CBC with
smear results about the likelihood that this
patient has a vitamin B12 deficiency?
a. Her CBC and smear are abnormal so she must
have a B12 deficiency.
b. Her CBC and smear are normal so she does not
have a B12 deficiency.
c. A normal CBC and smear do not rule out a B12
deficiency.
d. Nothing; it was a mistake to order a CBC and
smear in the first place.
You obtain a serum B12 level. Her results are:
Serum B12 211 (211-911)
pg/mL
5.
What does this patientвЂ™s serum B12 result
suggest?
a. Her result is within normal limits so she does
not have a vitamin B12 deficiency.
62
Vitamin B12 Deficiency
b. She might have a vitamin B12 deficiency;
further testing could be useful.
c. None of the above.
6.
A serum B12 result might be misleading for
patients who:
a. Are on oral contraceptives
b. Are fasting
c. Have liver disease or renal disease
d. Answers (a) and (c)
7.
Setting aside issues of cost and patient
convenience, which one of the following
additional tests would you consider the most
informative at this time?
a. Serum homocysteine
b. Serum methylmalonic acid
c. Serum holotranscobalamin
d. Schilling test
You order additional tests during the workup for this
patient.
Other laboratory results:
TSH 2.3 (0.34вЂ“5.6) Вµ units/mL
ESR 23
(0вЂ“30) mm/Hr
CRP 3.1 (0вЂ“4.9) mg/L
Hcy 20
(4вЂ“17) Вµmol/L
MMA 0.71 (0.08вЂ“0.56) Вµmol/L
8.
Considering all of the evidence presented for
this patient, what would you do next?
a. Ask the patient to increase consumption of
animal food products and recheck her in 6
months
b. Ask the patient to take a multivitamin with B12
and recheck her in 6 months
c. Check for intrinsic factor antibodies and begin
treatment
d. Nothing
9.
Which of the following treatment options
would you select for this patient?
a. Intramuscular injections, starting with frequent
injections that are gradually tapered to monthly
injections
63
Vitamin B12 Deficiency
b. Oral formulation, same dosage throughout
c. Intramuscular injections initially, switching to
an oral formulation later
d. One of the above, depending on issues of cost,
convenience, and likely patient compliance
10.
Pernicious anemia was confirmed. How do
you advise this patient about her prognosis?
a. You tell her that a course of treatment with
vitamin B12 will cure her.
b. You advise her that she must continue
treatment with vitamin B12 for life.
c. You tell her that seaweed, nutritional yeast, and
algae will help prevent signs and symptoms
from occurring later.
d. A and C
e. None of the above
64